In many indications a medical product can be of advantage that comprises a hollow body, such as a medical stent, the wall of the hollow body being coated with a polymer, e.g. a polysaccharide such as chitosan.
A stent is a usually tubular object for insertion into a natural passage or conduit of the body, e.g. a blood-vessel, to prevent or counteract a localized flow constriction in said body passage or conduit. The wall of the stent often comprises a metal mesh, e.g. from metal wire, or a perforated metal sheet. Most stents are expandable in the sense that they can assume a compressed (or folded) state, in which they have a small tube cross-section for insertion into the body passage, and an expanded (or un-folded) state, which they can assume once introduced into the body passage and in which they have a larger cross-section in order to press against the walls of the body passage. The biocompatibility of medical products, in particular implantable medical products such as the before mentioned stents, can be improved by covering or coating them with a polymer, e.g. chitosan.
The polysaccharide chitosan is the N-deacetylated derivative of chitin, which can be found widely in the exoskeletons of arthropods, shells, crustaceans and the cuticles of insects. Chitosan, although naturally occurring in some fungi, is produced industrially by alkaline hydrolysis of chitin. The different solubilities of chitin and chitosan in dilute acids are commonly used to distinguish between the two polysaccharides. Chitosan, the soluble form, can have a degree of acetylation between 0% and about 60%, the upper limit depending on parameters such as processing conditions, molecular weight, and solvent characteristics. While soluble in acidic aqueous media, chitosan precipitates at a pH of above 6.3.
Both chitin and chitosan are promising polymers for a variety of applications, including water treatment (metal removal, flocculant/coagulant, filtration), pulp and paper (surface treatment, photographic paper, copy paper), cosmetics (make-up powder, nail polish, moisturizers, fixtures, bath lotion, face, hand and body creams, toothpaste, foam enhancing), biotechnology (enzyme immobilization, protein separation, chromatography, cell recovery, cell immobilization, glucose electrode), agriculture (seed coating, leaf coating, hydroponic/fertilizer, controlled agrochemical release), food (removal of dyes, solids and acids, preservatives, color stabilization, animal feed additive), and membranes (reverse osmosis, permeability control, solvent separation). Of particular interest are biomedical applications of chitin and chitosan because of their biocompatibility, biodegradability and structural similarity to the glycosaminoglycans. Applications and potential applications include wound dressings, tissue engineering applications, artificial kidney membranes, drug delivery systems, absorbable sutures, hemostats, antimicrobial applications, as well as applications in dentistry, orthopedics, ophthalmology, and plastic surgery. For comprehensive reviews of potential applications of chitin and chitosan see, for example Shigemasa and Minami, “Applications of chitin and chitosan for biomaterials” 1997, Biotech. Genetic. Eng. Rev. 1996, 13, 383, Kumar, “A review of chitin and chitosan applications”, React. Funct. Polym. 2000, 46 (1), 1 and Singh and Ray, “Biomedical applications of chitin, chitosan, and their derivatives”, J. Macromol. Sci. 2000, C40 (1), 69.
Due to its excellent biocompatibility, chitosan is a suitable candidate for biocompatible coatings in the medical field, such as for devices in urological, cardiovascular, gastrointestinal, neurological, lymphatic, otorhinolaryngological, ophthalmological and dental applications. For example, chitosan's regenerative potential towards endothelial cells (Chupa et al., “Vascular Cell Responses to Polysaccharide Materials: In Vitro and In Vivo Evaluations”, Biomaterials 2000; 21 (22), 2315) supports the formation of blood compatible layers when chitosan is applied to the surface of cardiovascular implants (see Thierry et al., “Biodegradable membrane-covered stent from chitosan-based polymers”, J. Biomed. Mater. Res. 2005; 75A (3); 556). Chitosan's bacteriostatic potential leads to a significant reduction of the risk of implant-related infections when applied as coating of vascular grafts (see Fujita et al., “Inhibition of vascular prosthetic graft infection using a photocrosslinkable chitosan hydrogel”, J. Surg. Res. 2004, 121 (1), 135). Another advantage of chitosan coatings is the option to incorporate bioactive agents such as cytostatic drugs which can be released in a controlled fashion (see Chen et al., “The characteristics and in vivo suppression of neointimal formation with sirolimus-eluting polymeric stents”, Biomaterials 2009, 30 (1), 79).
As to the coating of hollow medical products with polymers, the article by Thierry et al., supra, describes a method in which a metal stent is covered with a compact film by casting a jelly-like solution containing chitosan and polyethylene glycol onto the stent while the latter is rotated. The film covers the entire surface of the mesh-like stent, i.e. not only the struts but also the spaces between them. The latter can be disadvantageous as the chitosan layer between the struts may break when the stent changes from the compressed into the expanded state.
In the article “Feasibility evaluation of chitosan coatings on polyethylene tubing for biliary stent applications” by Lin et al., J. Appl. Poly. Sci. 2005, 97, 893-902 a method of manufacturing a biliary stent is described, in which a solid PE tube is covered on its inside with a chitosan layer. For this purpose, first a chitosan solution is injected into the tube and after one hour replaced with methanol. After removal of the methanol, the tube was dried, neutralized and further dried. It may be a disadvantage of this prior art method that it is not suitable for holey stents for the reason described above.
In the U.S. Pat. No. 7,279,174 a method is described in which a mixture of a hydrophobic polymer and a hydrophilic polymer such as chitosan is sprayed onto a stent in order to apply a chemically cross-linked networks of these polymers. It may be a disadvantage of this prior art that cross-linking and other modifications of chitosan can negatively affect the polymer's advantageous properties, in particular its biocompatibility. The U.S. Pat. No. 7,255,891 suggests dipping a stent into a polymer solution such as a chitosan solution or spraying it with that solution. Similarly, the U.S. Pat. No. 6,899,731 describes an experiment in which alternation layers of chitosan and DNA were applied to a balloon catheter by means of spraying or dipping. It is suggested that such alternating layers could also be applied to stents. The U.S. Pat. No. 6,555,225 discloses the formation of mechanically stable layers on a stent surface of a polyelectrolyte complex that comprises a water-soluble polyion such as chitosan iconically cross-linked to a water-insoluble polyion.
The U.S. Pat. No. 6,969,400 suggests applying to a synthetic implant such as a stent a mixture of chitosan and two other polymer components forming a covalently cross-linked network. In the U.S. Pat. No. 7,351,421 a method is described in which a chitosan solution is applied to a stent, e.g. by dip coating or spray coating, and a cross-linking agent is subsequently applied in order to covalently cross-link the chitosan. The U.S. Pat. Nos. 6,923,996 and 7,390,525 describe a method in which first a reactive layer comprising a cross-linking agent is applied on the surface of a medical device, such as a stent, followed by the application of a solution comprising a drug and a cross-linkable polymer, such as chitosan. Finally, the article by Thierry et al. “Bioactive coatings of endovascular stents based on polyelectrolyte multilayers”, Biomacromolecules, 2003, 4 (6), 1564, describes a method in which a NiTi stent was first provided with a PEI primer layer and then alternating layers of hyaluronan and chitosan.
The article by Wu et al. “Voltage-dependent assembly of the polysaccharide chitosan onto an electrode surface”, Langmuir, 2002, 18 (22), 8620, and the article by Fernandes et al. “Electrochemically induced deposition of a polysaccharide hydrogel onto a patterned surface” Langmuir, 2003, 19 (10), 4058 describe the electro-deposition of chitosan on negatively charged electrodes in an acidic aqueous chitosan solution. The U.S. Pat. Nos. 7,014,749 and 7,387,846 disclose methods for electrolytically depositing a mixture of chitin and brushite (a pre-cursor of hydroxyapatite) on a metallic prosthesis.
The international patent application WO 01/014617 describes an electrodeposition method in which a stent acting as working electrode, a reference electrode, and a counter-electrode are submerged in an electrolyte comprising chitosan. It is suggested that radioactively labelled chitosan may be deposited on the stent if the stent plays the role of the cathode. The inventors seek to exploit the fact that the presence of radioactivity on the surface of the stent can reduce the incidence of restenosis.